Two new studies have identified new genes linked to autism and reveal differences in genetic influences between people along the autism spectrum. Scientists have used data from the SPARK research cohort (‘Simons Powering Autism Research’), created to contribute to the understanding of the complex genetics of autism spectrum disorders (ASD) and it collects genetic data from almost 43,000 individuals with autism.
“Autism is a spectrum and includes people with profound autism who often have cognitive differences or epilepsy, as well as people who are talented and exceptional, often in specific areas. We are now appreciating that the genetic contributions to different phenotypes vary in terms of the genes involved, when those genes are activated during brain development, and how common some of the genetic variants are in the population,” said Dr. Wendy Chung. , SPARK Principal Investigator.
In one of the studies published in Nature Genetics (“Integration of inherited and de novo variants in 42,607 cases of autism identifies mutations in new genes of moderate effect”), the DNA of almost 42,607 people with autism, including 35,000 study participants, was analyzed. SPARK autism research group, to understand the full spectrum of autism genetics. This autism cohort is the largest studied to date and allowed researchers to identify a group of new “moderate effect” genes that tend to contribute to autism through inherited variants.
“Autism is a spectrum and includes people with profound autism who often have cognitive differences or epilepsy, as well as people who are talented and exceptional, often in specific areas”
Autism is known to run in families, but previous research has mostly identified autism genes with de novo variants (DNVs), which occur spontaneously in germ cells before conception, ie they are not inherited. Most of the genetic variants of this type related to autism have a profound impact on the brain of those affected when they occur. However, only 20% of individuals with autism have this type of genetic variant.
“For many years, we have known from twin studies that there must be inherited genetic variants that lead to autism, but until now we have not been able to systematically identify individual genes,” said lead author Pamela Feliciano, SPARK chief scientific officer. “We have now identified a group of genes associated with autism, which may include inherited variants, that begin to explain a different part of the autism spectrum.”
The researchers studied 19,843 participants with autism, along with one or both of their biological parents, and found that around 20% of people with autism have de novo genetic variants that influence the function of the associated gene. Nearly 70% of this genetic contribution can be attributed to genes known for autism or neurodevelopmental disorders, but this means that while genes known to be associated with autism are responsible for the majority of de novo variants, there are others that have not yet been identified.
These scientists then added another 22,764 people with autism and 236,000 people without autism from the general population. They thus identified 60 autism genes whose contribution to autism is mainly due to rare variants of inherited loss of function (LOF) that are transmitted by parents who do not have cognitive alterations, nor autism. Five of these genes had not previously been involved in neurodevelopmental problems.
Individuals with autism who carry inherited variants in these “moderate effect” genes are less likely to have cognitive differences than individuals with autism who carry LOF variants in well-established autism genes, such as CHD8 and SCN2A.
“Most of the parents who passed on these gene variants in our study have no cognitive differences, no autism, but we know that these genes are associated with autism because we found that these variants are more frequently inherited by children with autism. Our hypothesis was that people with autism who have these inherited genetic variants are not as likely to have seizures or cognitive differences as people with de novo genetic variants. So far, our data strongly support this hypothesis”, said Dr. Feliciano.
Genes more associated with autism than with other neurological disorders
The other study, called ‘Rare coding variation provides insight into the genetic architecture and phenotypic context of autism’, and also published in Nature Genetics, has been conducted by a team of scientists supported by the Autism Sequencing Consortium, the Simons Foundation Autism Research Initiative, the Lundbeck Foundation Initiative for Integrative Psychiatric Research, the Population-Based Genetics and Environment Study of Autism, and the Massachusetts Institute of Technology Genomics Center for Common Diseases ( USA).
These scientists analyzed genetic data from 20,627 people with autism, with new genetic data obtained primarily from SPARK. They developed new techniques to discover DNA gains and losses, or copy number variants (CNVs), from exome sequencing, and methods to integrate data from these CNVs with other classes of rare and de novo inherited variants, and identified 72 genes associated with autism. Most of the evidence came from de novo variants, with smaller but significant contributions from rare inherited variants.
They then combined the data from the autism studies with a large data set of 31,000 families with a child diagnosed with a developmental delay or other neurodevelopmental conditions. 373 genes associated with these various neurodevelopmental outcomes were discovered, and the team was able to identify genes more closely related to autism than other neurodevelopmental problems, and vice versa. They found that genes predominantly associated with developmental delay are often important in early neuronal development, while genes for autism are likely to play a role in more mature neurons.
“We now have more insight into the biology of the brain changes that underlie autism and more potential targets for treatment.”
The researchers then combined the data from the autism studies with a large data set of 31,000 families in which the child was diagnosed with a developmental delay and/or other neurodevelopmental conditions. These analyzes uncovered 373 genes associated with these various neurodevelopmental outcomes and allowed the team to identify genes more associated with autism than other neurodevelopmental conditions, and vice versa. They found that genes associated predominantly with developmental delay tend to be important in early neuronal development, while autism genes tend to play a role in more mature neurons.
The study’s lead author, Michael Talkowski, director of the Center for Genomic Medicine at Massachusetts General Hospital and a member of the Broad Institute, said: “These analyzes suggested that most of the identified genes play a very early role in brain development. , although genes with higher mutation rates in autism showed slightly higher enrichment in more mature excitatory neurons. There are so many new genes and neurodevelopmental insights to be sought from these findings, and all of these discoveries were only made possible because of the accessibility of [los] rich data that SPARK and other studies provide for the field.”
The discoveries help understand the molecular roots of brain development and neurodiversity, and provide new avenues for research into the biology of autism. “We know that many genes, when mutated, contribute to autism, and in this unprecedented study we were able to bring together multiple types of mutations across a wide range of samples to gain a much richer picture of the genes and genetic architecture involved in autism and other neurodevelopmental conditions. This is significant because we now have more insight into the biology of the brain changes that underlie autism and more potential targets for treatment,” said Joseph D. Buxbaum, director of the Center for Autism Research and Development at Mount Sinai Hospital. USA).
Buxbaum adds that using precision medicine to address autism treatment would benefit patients, since therapies that work for people who have a mutation in one gene may not work for those who have a mutation in a different gene. “A key takeaway is that autism has many genetic mutations driving it, and therefore genetic testing is warranted, not only for the benefit of families and individuals at risk for autism spectrum disorder, but also to promote the development of therapies”, highlights Buxbaum.
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